Interstitial cystitis, also known as painful bladder syndrome, is a pathological condition that affects as many as 1 million patients in the U.S. with a high incidence in females. A heterogeneous array of symptoms varies from case to case and even in the same individual. Such symptoms can include mild discomfort, pressure, tenderness, intense pain in the bladder and pelvic area, increased urinary frequency/urgency, nocturia or a combination of these symptoms12. Pain may change in intensity as the bladder fills with urine or as it empties. People with interstitial cystitis also have a defect in the protective lining (transitional epithelium; also urothelium) of the bladder. The loss of the integrity of the urothelium is suspected to lead to leaky epithelium lining the bladder wall and allow toxic substances in urine to irritate the bladder wall.
The etiology of IC is complex including inflammation, infection, hormone involvement, autoimmunity, psychological effects, and genetic implications. The pathogenesis of IC involves inflammation, neural changes, urothelial dysfunctions, hypersensitivity, fibrosis, oxidative stress and apoptosis in the development and progression of this painful bladder syndrome. Tomazewski et al.2 investigated the association between the pathologic changes in the bladder biopsies with urinary bladder dysfunction among 204 IC patients enrolled in the Interstitial Cystitis Database (ICDB). The pathologic changes noted were increased number of mast cells in the lamina propria, loss of urothelium, granulation tissue and increased vascular density in the lamina propria, and submucosal hemorrhage. Thus, the lesion in the bladder appears to center in the epithelium and the lamina propria of the bladder.
Patients with IC have substantially lower cystometric bladder volumes compared to normal women (265 ml versus 586 ml) and first voiding desire is at 74 ml compared to 315 ml for normal3,4. This suggests that the mechanoreceptors and chemoreceptors in the bladder of IC patients may be altered, and this may trigger myelinated A-δ fibers or C-fibers found in the detrusor smooth muscle or the submucosa in response to bladder distention5,6. Although there are several hypotheses to account for the pathogenesis of IC, a widely accepted theory focuses on urothelial dysfunction. The urothelium, covered by proteoglycan and uroplakin, prevents the adhesion of infectious organisms, and the entrance of irritating urinary solutes into the interstitium7. A glycosylated frizzled-related peptide (APF) which inhibits the proliferation of urothelial cell is secreted by urothelial cells from patients with IC8. A defective urothelium is less protective, allowing urinary solutes like potassium to leak into the mucosa and submucosal region9. This can lead to activation of C-fibers, release of substance P and mast cell degranulation and subsequent injury to the submucosal tissue. These tissue changes lead to neuronal activation, leading to urinary urgency/frequency and pelvic pain associated with IC10.
Current diagnostic tests for IC include urinalysis for evidence of a urinary tract infection, urine culture and cytology, and potassium sensitivity tests. Still other diagnostic tests include cystoscopy, i.e., an examination of the bladder through a cystoscope inserted through the urethra. Additionally, cystodistension performed with anesthetics can determine the bladder's capacity. In males, a diagnostic procedure can include laboratory examination of prostate secretions.
It is difficult to make a clear diagnosis of IC because clinicians are hampered by the lack of biomarkers to either evaluate the symptoms, pathological changes, and pathogenesis of the condition and/or to provide appropriate treatments. Even when a mode of treatment is selected and tried, it is difficult to evaluate the effect of treatment for inducing beneficial changes in the bladder wall, the urothelium and the suburothelial regions, which are severely affected in IC. Most biomarkers for IC or related syndromes that were analyzed in the past were inflammatory cytokines (such as IL-Iβ, IL-6, TNFα). Significant levels of IL-6 were found in the urine and bladder wall of patients in one study14. Another study34, 35 suggested the difficulty of correlating urine biomarkers such as IL-6 and IL-8 and biopsy findings, although a strong association between urine IL-8 and bladder mast cell count was found.
The presence of an anti-proliferative factor (APF), a low molecular weight sialoglycopeptide, and potent inhibitor of the growth of normal urothelial cells and bladder cancer cells8 was documented in the urine of patients with IC. The specificity of APF in urine from patients with IC (versus normal controls and patients with a variety of other urogenital disorders) indicates that it may be a useful biomarker for IC. A recent publication41 referred to gene expression profiles of bladder tissues of patients with ulcerative IC. This study used very little urothelium because the urothelial layer was denuded due to ulceration.
There remains a need in the art for simpler, less invasive and more accurate diagnostic assays for IC, as well as for new and more effective treatments of this disorder.